Abstract
Copper (Cu) has emerged as an important modifier of body lipid metabolism. However, how Cu contributes to the physiology of fat cells remains largely unknown. We found that adipocytes require Cu to establish a balance between main metabolic fuels. Differentiating adipocytes increase their Cu uptake along with the ATP7A-dependent transport of Cu into the secretory pathway to activate a highly up-regulated amino-oxidase copper-containing 3 (AOC3)/semicarbazide-sensitive amine oxidase (SSAO); in vivo, the activity of SSAO depends on the organism’s Cu status. Activated SSAO oppositely regulates uptake of glucose and long-chain fatty acids and remodels the cellular proteome to coordinate changes in fuel availability and related downstream processes, such as glycolysis, de novo lipogenesis, and sphingomyelin/ceramide synthesis. The loss of SSAO-dependent regulation due to Cu deficiency, limited Cu transport to the secretory pathway, or SSAO inactivation shifts metabolism towards lipid-dependent pathways and results in adipocyte hypertrophy and fat accumulation. The results establish a role for Cu homeostasis in adipocyte metabolism and identify SSAO as a regulator of energy utilization processes in adipocytes.
Highlights
Cu is required for numerous cellular functions, and the loss of Cu homeostasis is incompatible with life [1, 2]
The mRNA for superoxide dismutase 1 (SOD1; the main Cu-binding enzyme in the cytosol) was increased 3-fold in response to differentiation, whereas the transcripts of the cytosolic copper chaperone for superoxide dismutase (CCS) and antioxidant 1 copper chaperone (Atox1) were not significantly changed (Fig 1B)
We show that Cu transfer to the secretory pathway and activation of sensitive amine oxidase (SSAO) is a prerequisite for establishing a balanced energy utilization in differentiating adipocytes
Summary
Cu is required for numerous cellular functions, and the loss of Cu homeostasis is incompatible with life [1, 2]. Cu-dependent enzymes critically contribute to mitochondria respiration, cellular defense against oxygen radicals, angiogenesis, wound healing, biosynthesis of neuromodulators, and many other processes [3]. Increasing evidence points to a tight functional link between Cu homeostasis and lipid metabolism. Cu accumulation in the liver alters the tissue levels of triglyceride and cholesterol [4, 5], and, reciprocally, excess fat decreases the hepatic Cu content [6, 7].
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